EP2445909B1 - DÉRIVÉS AMIDES DE L'ACIDE 6,7-DIHYDRO-5H-IMIDAZO[1,2-a]IMIDAZOLE-3-CARBOXYLIQUE - Google Patents

DÉRIVÉS AMIDES DE L'ACIDE 6,7-DIHYDRO-5H-IMIDAZO[1,2-a]IMIDAZOLE-3-CARBOXYLIQUE Download PDF

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EP2445909B1
EP2445909B1 EP10720512.2A EP10720512A EP2445909B1 EP 2445909 B1 EP2445909 B1 EP 2445909B1 EP 10720512 A EP10720512 A EP 10720512A EP 2445909 B1 EP2445909 B1 EP 2445909B1
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ocf
mmol
methyl
optionally substituted
cyclopropyl
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EP2445909A1 (fr
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Rene Marc Lemieux
Steven Richard Brunette
Joshua Courtney Horan
Jennifer A. Kowalski
Michael David Lawlor
Bryan Mckibben
Craig Andrew Miller
Antonio J.M. Barbosa
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Boehringer Ingelheim International GmbH
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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Definitions

  • the present invention relates generally to a series of novel derivatives of 6,7-dihydro-5 H -imidazo[1,2- a ]imidazole-3-carboxylic acid amides, the synthesis of these compounds their use in the treatment of inflammatory disease and pharmaceutical compositions comprising these compounds.
  • integrins constitutively expressed on leukocytes
  • LFA-1 integrin-1
  • ICAM-2 intercellular adhesion molecules
  • ICAM-3 distinct intercellular adhesion molecules
  • Immune processes such as antigen presentation, T-cell mediated cytotoxicity and leukocyte extravasation all require cellular adhesion mediated by ICAMs interacting with the Leukointegrins. See generally Kishimoto, T. K.; Rothlein; R. R. Adv. Pharmacol. 1994, 25, 117-138 and Diamond, M.; Springer, T. Current Biology, 1994, 4, 506-532 .
  • Leukocyte Adhesion Deficiency I a condition termed "leukocyte Adhesion Deficiency I" ( Anderson, D. C.; et al., Fed. Proc. 1985, 44, 2671-2677 and Anderson, D. C.; et al., J. Infect. Dis. 1985, 152, 668-689 ). These individuals are unable to mount a normal inflammatory and/or immune response(s) due to an inability of their cells to adhere to cellular substrates. These data show that immune reactions are mitigated when lymphocytes are unable to adhere in a normal fashion due to the lack of functional adhesion molecules of the CD 18 family.
  • LFA-1 deficient lymphocytes are characterized by defects in aggregation and proliferation. In vivo parallel deficits in delayed type hypersensitivity (DTH) responses are observed. In animal models of organ transplantation, anti-LFA-1 antibodies have shown efficacy. Taken together these studies provide support for the role of LFA-1 in initiating and/or propagating inflammatory responses ( Giblin, P.A. et al. Curr. Pharm. Design, 2006, 12: 2771-2795 ).
  • antagonism of the interaction between the ICAMs and the Leukointegrins can be realized by agents directed against either component.
  • blocking of the CAMs, such as for example ICAM-1, or the Leukointegrins, such as for example LFA-1 by antibodies directed against either or both of these molecules effectively inhibits inflammatory responses.
  • ICAMs or Leukointegrins include antigen or mitogen-induced lymphocyte proliferation, homotypic aggregation of lymphocytes, T-cell mediated cytolysis and antigen-specific induced tolerance. The relevance of the in vitro studies is supported by in vivo studies with antibodies directed against ICAM-1 or LFA-1.
  • Odulimomab showed efficacy in clinical trials of bone marrow transplant ( Stoppa AM et al., Transpl Int 1991; 4(1):3-7 ) and in kidney transplant clinical trials ( Hourmant M et al. Transplantation 1994; 58(3):377-380 ).
  • the humanized anti-LFA-1 antibody Raptiva® (anti-CD11a, hu1124, efalizumab), marketed for psoriasis has provided the clinical proof of concept for the role of LFA-1 ( Leonardi CL et al., J Am Acad Dermatol 2005; 52(3 Pt 1):425-433 ).
  • US Patent 6,492,408 (and corresponding WO 01/07440 Al ), US Patent 6,844,360 , US Patent 6,852,748 , US Patent 7,517,897 and US Patent Application Publication 2006/0229287 all disclose compounds having this same activity that instead have a 6,7-dihydro-5 H -imidazo[1,2-a]imidazole core and inhibitors with a 1 H -imidazo-[1,2-a]imidazol-2-one core are disclosed by J-P Wu, et al., J. Med Chem. 2004; 47(22) 5356-5366 .
  • the invention comprises a novel class of derivatives of 6,7-dihydro-5 H -imidazo[1,2- a ]imidazole-3-carboxylic acid amides and methods for making the same. These compounds are useful for the treatment of inflammatory conditions in that they exhibit good inhibitory effect upon the interaction of ICAMs and Leukointegrins. They are also expected to have an improved metabolic profile over known LFA-1 antagonists while maintaining good functional LFA-1 antagonism in a whole blood environment. Thus, the invention further comprises these compounds for use in the treatment of inflammatory conditions and pharmaceutical compositions comprising the same as active ingredients.
  • C 1-4 alkyl is a saturated aliphatic hydrocarbon monovalent radical containing 1-4 carbons such as methyl, ethyl, n -propyl, 1-methylethyl (isopropyl), n -butyl or t -butyl. All alkyl groups shall be understood as being branched or unbranched, where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
  • the compounds of the invention are only those which are contemplated to be 'chemically stable' as will be appreciated by those skilled in the art.
  • a compound which would have a 'dangling valency', or a 'carbanion' are not compounds contemplated by the inventive methods disclosed herein.
  • Each stereogenic carbon may be in the R or S configuration, or a combination of configurations.
  • Some of the compounds of formula (I) can exist in more than one tautomeric form. The invention includes methods using all such tautomers.
  • the compounds of the invention and their salts include asymmetric carbon atoms and may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers.
  • such compounds will be prepared as a racemic mixture. If desired, however, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures using methods well know in the art.
  • individual stereoisomers of compounds may be prepared by synthesis from optically active starting materials containing the desired chiral centers or by preparation of mixtures of enantiomeric products followed by separation or resolution, such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, use of chiral resolving agents, or direct separation of the enantiomers on chiral chromatographic columns.
  • Starting compounds of particular stereochemistry are either commercially available or are made by the methods described below and resolved by techniques well-known in the art.
  • Preparation of pure enantiomers or mixtures of desired enantiomeric excess (ee) or enantiomeric purity are accomplished by one or more of the many methods of (a) separation or resolution of enantiomers, or (b) enantioselective synthesis known to those of skill in the art, or a combination thereof.
  • These resolution methods generally rely on chiral recognition and include, for example, chromatography using chiral stationary phases, enantioselective host-guest complexation, resolution or synthesis using chiral auxiliaries, enantioselective synthesis, enzymatic and nonenzymatic kinetic resolution, or spontaneous enantioselective crystallization.
  • the compounds of the invention are meant to embrace compounds of Formula (I) as herein described, as well as the pharmaceutically acceptable salts thereof.
  • salt means an ionic form of the parent compound or the product of the reaction between the parent compound with a suitable acid or base to make the acid salt or base salt of the parent compound.
  • Salts of the compounds of the present invention can be synthesized from the parent compounds which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid parent compound with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
  • pharmaceutically acceptable salt means a salt of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, generally water or oil-soluble or dispersible, and effective for their intended use.
  • pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • the compounds of the present invention are useful in both free base and salt form, in practice, the use of the salt form amounts to use of the base form. Lists of suitable salts are found in, e.g., S.M. Birge et al., J. Pharm. Sci., 1977, 66, pp. 1-19 , which is hereby incorporated by reference in its entirety.
  • acids for preparing salts include hydrochloric, hydrobromic, carbonic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2-sulfonic and benzenesulfonic acids.
  • Other acids, such as oxalic acid while not themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of this invention and their pharmaceutically acceptable acid addition salts.
  • Salts derived from appropriate bases include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium and N-(C 1-4 alkyl) 4 + salts.
  • the invention relates to a compound selected from compounds described in Table 1, or the pharmaceutically acceptable salts thereof.
  • the invention relates to a compound selected from compounds 1, 2, 4-8, 10-16, 18, 20, 21, 23, 27, 28, 30-35, 37-47, 49-52, 54, 56, 58, 60-62, 64-66, 68-70, 72, 75, 78, 87-90, 93, 96, 100, 101, 103-106, 108-112, 115-121, 123, 125, 127, 129, 131-136, 138, 141-143, 145, 146 and 149-160 in Table 1, or the pharmaceutically acceptable salts thereof.
  • the compounds of the invention may be prepared by the methods described below.
  • the groups R 1 - R 8 , Y and Z are as defined above for general formula I unless noted otherwise.
  • Optimum reaction conditions and reaction times may vary depending on the particular reactants used. Unless otherwise specified, solvents, temperatures, pressures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Synthetic Examples section. Typically, reaction progress may be monitored by thin layer chromatography (TLC) or HPLC-MS if desired. Intermediates and products may be purified by chromatography on silica gel, recrystallization and/or reverse phase HPLC. HPLC purification methods used anywhere from 0-100% acetonitrile in water containing 0.1% formic acid or 0.1% TFA and used one of the following columns:
  • Carboxylic acid III provides I by either amide formation with a suitably functionalized intermediate V, or a two step procedure which forms intermediate IV prior to final amide forming reaction with intermediate VII or elaboration of IV to IX by amide formation followed by cross coupling.
  • Intermediates (V, VI, VII and VIII) are either commercially available, readily prepared from commercially available starting materials by methods known in the art or disclosed herein.
  • the initial product of formula I may be further modified by methods known in the art to provide additional compounds of the invention. Several examples are provided in the Synthetic Examples section.
  • the resulting pale yellow reaction mixture was stirred at room temperature for 30 min and then heated at 100 °C for 16 h.
  • the clear pale orange reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (2 x 20 mL). The organics were washed with of water (2 x 15 mL) and brine (15 mL), dried over Na 2 SO 4 , filtered, and concentrated to a crude oil.
  • reaction suspension was filtered and the solid was washed with ether (10 mL) to afford 1-[5-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-pyridin-2-yl]-cyclopropylamine HCl salt (40 mg) as a white solid.
  • the tube was sealed and heated in microwave at 100 °C for 10 minutes and then 120 °C for 20 minutes. 2M NaOH was added (2 mL) and stirred for 10 minutes. The solution was extracted with EtOAc (100 mL). The organic phase was washed with brine, dried over MgSO 4 , filtered through diatomaceous earth, and concentrated.
  • Impure 2-methyl-propane-2-sulfinic acid [1-(6-chloro-pyridazin-3-yl)-1-methyl-ethyl]-amide (15 mg, 0.054 mmol) was combined with Pd(dppf)Cl 2 ⁇ dichloromethane complex (4.7 mg, 0.006 mmol), 1M K 3 PO 4 (0.07 mL, 0.07 mmol) and 2-(hydroxymethyl)pyridine-5-boronic acid (18 mg, 0.12 mmol) in a microwave vial.
  • a 7:3:2 mixture of DME/H 2 O/EtOH (1 mL) was added. The vial was flushed with argon and sealed.
  • HATU (386 mg, 1.01 mmol) was added, and the clear yellow reaction mixture was stirred at room temperature for 3 h.
  • the reaction mixture was partitioned between 75 mL of ethyl acetate and 25 mL of water.
  • the organic phase was washed with 2 ⁇ 25 mL of 5% aqueous NaCl solution and 25 mL of brine, dried over Na 2 SO 4 , filtered, and concentrated in vacuo.
  • the residue was purified by flash chromatography on silica gel, eluting with 0-3% MeOH in CH 2 Cl 2 , to provide 653 mg (98%) of title compound as a yellow foam, m / z 726.4 [M +1] + .
  • Boc-1-aminocyclobutane-1-carboxylic acid (10.0 g, 45.1 mmol), HATU (20.5 g, 54.1 mmol) and N , O -dimethylhydroxylamine hydrochloride (4.93 g, 49.6 mmol) were combined in DMF (100 mL).
  • diisopropylethylamine (31.4 mL, 180.3 mmol).
  • the reaction was stirred for 2 h, diluted with EtOAc and poured into H 2 O.
  • the aqueous phase was separated and extracted two more times with EtOAc.
  • the organic layers were combined and washed with brine, dried (Na 2 SO 4 ), decanted and concentrated in vacuo.
  • the filtrate was concentrated in vacuo and reprocessed in a similar manner to obtain additional precipitate.
  • the remaining filtrate was diluted with hexane until a black oil separated from the solution.
  • the hexane layer was decanted from this black oil and concentrated in vacuo.
  • the residue was re-dissolved in warm diethyl ether (300 mL) and stored in the freezer for 1.5 h over which time crystal growth was observed.
  • the solids were filtered, and the filtrate reprocessed in a similar manner to obtain additional crystals.
  • the reaction mixture was stirred at 0 °C for 1 h and then warmed to 20 °C over 1 h. The mixture was then cooled to 10 °C and water (1.2 L) was added. The layers were separated and the organic layer was washed with water (1.2 L and then 0.6 L). The combined aqueous layers were extracted with toluene (0.6 L). The combined organic layers were dried over MgSO 4 and concentrated in vacuo to give 149.4 g of the title compound as a tan solid, m / z 456.4 [M+MeCN+H] + .
  • Both reagents were added at a rate sufficient to keep the internal temperature at 0 °C.
  • the reaction mixture was stirred at this temperature for 6.5 h.
  • HCl solution (6N, 234 mL, 1.40 mol) was then added to the reaction mixture at a rate sufficient to keep the internal temperature below 15 °C.
  • the reaction was heated to 50 °C and stirred at this temperature for 1.5 h.
  • a portion of the solvent ( ⁇ 350 mL) was removed in vacuo and CH 2 Cl 2 (300 mL) was added.
  • the mixture was cooled in an ice bath and a NaOH solution (2N) was added at a rate to keep the internal temperature below 20 °C until the pH of aqueous layer reached 14.
  • the solution was cooled to 20 °C and transferred to a separatory funnel with aqueous Na 2 CO 3 (3 wt%, 500 mL) and EtOAc (500 mL), forming a triphasic system after shaking. The bottom two layers were removed. The top organic layer was washed with 3% aqueous NaCl (500 mL), dried with Na 2 SO 4 and concentrated in vacuo keeping internal temperature lower than 40 °C. A mixture of heptane and EtOAc (10:1 heptane:EtOAc, 20 mL) was added and the resulting slurry was stirred at 22 °C for 16 h.
  • Acetic anhydride (14.0 mL, 148 mmol), sodium formate (15.1 g, 222 mmol) and Hunig's base (25.8 mL, 148 mmol) were suspended in anhydrous DMF (50 mL) in a 1000 mL screw-top glass pressure-vessel. This was sealed with the screw cap and allowed to stir for 45 min at room temperature.
  • HATU (845 mg, 2.22 mmol) was then added, and the clear yellow reaction mixture was stirred at room temperature for 21 h.
  • the reaction mixture was partitioned between 150 mL of ethyl acetate and 50 mL of 1M HCl. The organic phase was washed with satd. NaHCO 3 solution, water (2 ⁇ ), and brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • reaction mixture was then diluted with 30 mL of EtOAc and washed with 10 mL each of 10% HCl solution, water, and brine, dried over Na 2 SO 4 , filtered, and concentrated.
  • the residue was applied to a SiliaBond Carbonate preloaded cartridge (2 g, 0.7 mmol/g, Silicycle).
  • the column was eluted with 30 mL of 10% MeOH in CH 2 Cl 2 followed by 200 mL of 0.1:1:9 TFA/MeOH/CH 2 Cl 2 to furnish 142 mg 76%) of the title compound as a colorless foam, m/z 579.4 [M + 1] + .
  • a microwave vial was charged with 1- ⁇ [(R)-5-(4-bromo-benzyl)-7-(3,5-dichlorophenyl)-5-methyl-6-oxo-6,7-dihydro-5 H -imidazo[1,2- a ]imidazole-3-carbonyl]-amino ⁇ -cyclopropanecarboxylic acid allyl ester (400 mg, 0.647 mmol), NiCl 2 •6H 2 O (231 mg, 1.22 mmol), and 1.5 mL of DMF. The vial was sealed and heated in the microwave at 170 °C for 40 min, and then for 1 h.
  • the crude reaction mixture was diluted with 30 mL of EtOAc and 15 mL of water (the solids were not soluble). The aqueous phase was extracted with 10 mL of EtOAc. The combined organics were washed with 5% NaCl solution (2 ⁇ 15 mL) and brine, dried over Na 2 SO 4 , filtered, and concentrated to afford 299 mg of a cloudy green oil, isolated as a ⁇ 1:1 mixture of the aryl bromide and the aryl chloride.
  • the crude bromide/chloride acid mixture ( ⁇ 0.25 mmol) was concentrated in a microwave vial. To this mixture was added 3-pyridyl boronic acid (45 mg, 0.37 mmol), Pd(dppf)Cl 2 ⁇ dichloromethane complex (20 mg, 0.024 mmol), 4 mL of DME/H 2 O/EtOH (7/3/2), and aqueous K 3 PO 4 solution (0.73 mL, 1M, 0.73 mmol). The vial was sealed and heated in the microwave at 100 °C for 15 min, followed by heating at 130 °C for an additional 30 min. The reaction mixture was then filtered through a plug of silica gel, washing with 10 mL of MeOH, and concentrated.
  • reaction mixture was purified by reversed phase MPLC (C18, 30g, Mobile phase: CH 3 CN (0.1% TFA), water (0.1% TFA), Gradient: 70% water to 10% water).
  • the pure fractions were combined and concentrated in-vacuo to remove most of the CH 3 CN and then partitioned between 50 mL of CH 2 Cl 2 , 20 mL of water, and 10 mL of saturated aqueous NaHCO 3 solution.
  • This assay protocol is designed to study the direct antagonism, by a test compound, of the interaction of ICAM-1 with the Leukointegrin CD18/CD11a (LFA-1).
  • the LFA-1/Biotin-sICAM-1 molecular assay measures the ability of test compounds to inhibit binding of LFA-1 to Biotinylated-sICAM using AlphaScreen technology (Ref: Wilson, J, Rossi, CP, Carboni, S, Fremaux, C, Perrin, D, Soto, C, Kosco-Vilbois, M, and Scheer, A: A Homogeneous 384-Well High-Throughput Binding Assay for a TNF Receptor Using Alphascreen Technology. J Biomol Screen 2003;8:522-532 ) that uses TS2/4(anti-LFA-1)-custom conjugated AlphaLisa acceptor beads and streptavidin-coated donor beads from PerkinElmer.
  • the assay was performed in white OptiPlates-384 in a volume of 60 ⁇ L using assay buffer (Dulbecco's PBS containing calcium and magnesium, 2 mM MgCl2, 0.1 mM PMSF, 0.1% BSA, pH 7.1).
  • assay buffer Dulbecco's PBS containing calcium and magnesium, 2 mM MgCl2, 0.1 mM PMSF, 0.1% BSA, pH 7.1.
  • Biotin-sICAM was added followed by purified LFA-1 (in buffer of 50 mM triethylamine, 150 mM NaCl, 1% beta octylglucoside, 2 mM MgCl 2 neutralized to pH with 1M Tris-HCl, pH 7.5).
  • LFA-1 in buffer of 50 mM triethylamine, 150 mM NaCl, 1% beta octylglucoside, 2 mM MgCl 2 neutralized to pH with 1M Tris-
  • LFA-1 and Biotin-sICAM-1 were used at concentrations that would yield a signal to background ratio of 8-10.
  • the highest concentration of compound was 1 ⁇ M in 1% DMSO.
  • Positive controls were wells without compound containing LFA-1, while blanks were wells without both compound and LFA-1. Plates were mixed and incubated at 37 °C for 90 minutes. This was followed by addition of 15 ⁇ L/well TS2/4-congugated acceptor beads diluted in PBS containing 0.1% BSA for a final concentration of 10 ⁇ g/mL.
  • the plates were mixed and incubated in the dark for 30 minutes at room temperature followed by addition of 15 ⁇ L/well streptavidin-coated donor beads diluted in PBS containing 0.1% BSA at a final concentration of 15 ⁇ g/mL.
  • the plates were mixed and incubated in the dark for 60 minutes at room temperature and then read on an EnVision Multilabel Reader using AlphaScreen 384-well OptiPlate protocol.
  • This assay protocol is designed to study the functional antagonism, by a test compound, of the interaction of ICAM-1 with the Leukointegrin CD18/CD11a (LFA-1).
  • Compounds were evaluated for their ability to inhibit the production of IL-2 by cells present in freshly drawn heparinized human whole blood after stimulation ex vivo by staphylococcal enterotoxin B (SEB).
  • SEB staphylococcal enterotoxin B
  • Compounds were diluted in human AB serum to 11X their final assay concentration. Following further dilution for concentration response curves in human AB serum containing 1.12% DMSO, human whole blood was added to the compounds. Following a 30 minute incubation of blood and compound, SEB was then added to yield a final concentration of 600 ng/mL SEB and a final DMSO concentration of 0.1%. After overnight incubation (37 °C humidified CO 2 incubator), plasma samples were collected and analyzed for the presence of IL-2 using an electrochemiluminescence protocol.
  • a biotinylated anti-human IL-2 antibody (R&D Systems BAF202), an MSD Sulfo-TAG (MSD R91AN-2) labeled anti-human IL-2 monoclonal antibody (R&D Systems MAB602), and MSD Standard Avidin plates were employed to measure IL-2 in plasma samples.
  • This assay protocol is designed to study the stability of a test compound toward metabolic oxidation by human liver microsomes.
  • Percent loss of parent compound was calculated from the peak area ratio (compound/internal standard) at each time point in comparison to the peak area ratio of the zero minute sample to determine the t 1/2 in minutes.
  • novel small molecules of formula I provided by the invention inhibit the ICAM-1/LFA-1 dependent homotypic aggregation of human lymphocytes and human lymphocyte adherence to ICAM-1.
  • These compounds have therapeutic utility in the modulation of immune cell activation/proliferation, e.g., as competitive inhibitors of intercellular ligand/receptor binding reactions involving CAMs and Leukointegrins.
  • the compounds of the invention may be used to treat certain inflammatory conditions, including conditions resulting from a response of the specific immune system in a mammal (e.g., asthma, psoriasis, organ/tissue transplant rejection, graft vs.
  • the compounds of the invention can be used to treat psoriasis and multiple sclerosis
  • another aspect of the invention is directed to a compound of formula I for use as a medicament and, in a particular aspect, for use as a medicament for the treatment of inflammation or an inflammatory condition.
  • the invention is directed to a compound of formula I for use as a medicament for the treatment of any of the diseases or conditions listed in the previous paragraph.
  • the invention is directed to the use of a compound of formula I for the manufacture of a medicament for the treatment of any of the diseases or conditions listed in the previous paragraph.
  • the novel compounds of formula I may be administered for either a prophylactic or therapeutic purpose either alone or with other immunosuppressive or antiinflammatory agents.
  • the immunosuppressive compound(s) are provided in advance of any inflammatory response or symptom (for example, prior to, at, or shortly after the time of a relapse in multiple sclerosis).
  • the prophylactic administration of a compound of the formula I serves to prevent or attenuate any subsequent inflammatory response (such as, for example, a relapse in multiple sclerosis).
  • the therapeutic administration of a compound of the formula I serves to attenuate any actual inflammation (such as, for example, a relapse in multiple sclerosis).
  • a compound of the formula I can be administered either prior to the onset of inflammation (so as to suppress an anticipated inflammation) or after the initiation of inflammation.
  • novel compounds of the formula I may be administered in single or divided doses by the oral, parenteral or topical routes.
  • a suitable oral dosage for a compound of formula I would be in the range of about 0.1 mg to 10 g per day, preferably in the range of 1 mg to 100 mg per day.
  • a suitable dosage unit may contain from 0.1 to 250 mg of said compounds, whereas for topical administration, formulations containing 0.01 to 1% active ingredient are preferred. It should be understood, however, that the dosage administration from patient to patient will vary and the dosage for any particular patient will depend upon the clinician's judgement, who will use as criteria for fixing a proper dosage the size and condition of the patient as well as the patient's response to the drug.
  • the compounds of the present invention When the compounds of the present invention are to be administered by the oral route, they may be administered as medicaments in the form of pharmaceutical preparations which contain them in association with a compatible pharmaceutical carrier material.
  • a compatible pharmaceutical carrier material can be an inert organic or inorganic carrier material suitable for oral administration. Examples of such carrier materials are water, gelatin, talc, starch, magnesium stearate, gum arabic, vegetable oils, polyalkylene-glycols, petroleum jelly and the like.
  • the pharmaceutical preparations can be prepared in a conventional manner and finished dosage forms can be solid dosage forms, for example, tablets, dragees, capsules, and the like, or liquid dosage forms, for example solutions, suspensions, emulsions and the like.
  • the pharmaceutical preparations may be subjected to conventional pharmaceutical operations such as sterilization. Further, the pharmaceutical preparations may contain conventional adjuvants such as preservatives, stabilizers, emulsifiers, flavor-improvers, wetting agents, buffers, salts for varying the osmotic pressure and the like.
  • Solid carrier material which can be used include, for example, starch, lactose, mannitol, methyl cellulose, microcrystalline cellulose, talc, silica, dibasic calcium phosphate, and high molecular weight polymers (such as polyethylene glycol).
  • a compound of formula I can be administered in an aqueous or nonaqueous solution, suspension or emulsion in a pharmaceutically acceptable oil or a mixture of liquids, which may contain bacteriostatic agents, antioxidants, preservatives, buffers or other solutes to render the solution isotonic with the blood, thickening agents, suspending agents or other pharmaceutically acceptable additives.
  • Additives of this type include, for example, tartrate, citrate and acetate buffers, ethanol, propylene glycol, polyethylene glycol, complex formers (such as EDTA), antioxidants (such as sodium bisulfite, sodium metabisulfite, and ascorbic acid), high molecular weight polymers (such as liquid polyethylene oxides) for viscosity regulation and polyethylene derivatives of sorbitol anhydrides.
  • complex formers such as EDTA
  • antioxidants such as sodium bisulfite, sodium metabisulfite, and ascorbic acid
  • high molecular weight polymers such as liquid polyethylene oxides for viscosity regulation and polyethylene derivatives of sorbitol anhydrides.
  • Preservatives may also be added if necessary, such as benzoic acid, methyl or propyl paraben, benzalkonium chloride and other quaternary ammonium compounds.
  • the compounds of this invention may also be administered as solutions for nasal application and may contain in addition to the compounds of this invention suitable buffers, tonicity adjusters, microbial preservatives, antioxidants and viscosity-increasing agents in an aqueous vehicle.
  • suitable buffers tonicity adjusters
  • microbial preservatives antioxidants
  • viscosity-increasing agents in an aqueous vehicle.
  • agents used to increase viscosity are polyvinyl alcohol, cellulose derivatives, polyvinylpyrrolidone, polysorbates or glycerin.
  • Microbial preservatives added may include benzalkonium chloride, thimerosal, chloro-butanol or phenylethyl alcohol.
  • the compounds provided by the invention can be administered topically or by suppository.

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Claims (11)

  1. Composé de formule I :
    Figure imgb2013
     dans laquelle :
    R1 est sélectionné parmi -CN, -OCF3, -CF3, un halogène, un hétéroaryle facultativement substitué par un halogène ou un alkyle en C1 à 3 et un phényle facultativement substitué par un halogène.
    R2 est Cl ou -CF3 ;
    R3 est H ou un halogène ;
    X est un groupe
    Figure imgb2014
     dans lequel
    R4 est sélectionné parmi :
    (A) -H ;
    (B) un alkyle en C1 à 3 facultativement substitué par un ou deux groupes sélectionnés parmi :
    a) un cycloalkyle en C3 à 6 ;
    b) -OR9 ;
    c) -NR9R10 ;
    d) -SOR9 ;
    e) -S02R9;
    f) -C(O)NR9R10 ;
    g) -C(O)OR9 ;
    h) un hétéroaryle facultativement substitué par un alkyle en C1 à 3 ;
    i) un hétérocyclyle facultativement substitué par un alkyle en C1 à 3 ; et
    j) un phényle facultativement substitué par un alkyle en C1 à 3 ;
    (C) un cycloalkyle en C3 à 6 ;
    (D) un hétéroaryle ; et
    (E) un phényle facultativement substitué par un halogène, -OR9, -CN ou -CF3 ;
    R5 est H ou un alkyle en C1 à 3 ; ou
    R4 et R5, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 à 7 atomes de carbone et dans lequel un atome de carbone dans ledit cycle hydrocarboné peut être facultativement remplacé par -O-, -S-, -S(O)-, -SO2-, -NH-, -NCH3- ou -NC(O)CH3- ;
    Y est un groupe
    Figure imgb2015
     dans lequel R6 est H ou un alkyle en C1 à 3 ;

    R7 est H ou un alkyle en C1 à 3 ; ou
    R6 et R7, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 à 7 atomes de carbone dans lequel un atome de carbone dans ledit cycle hydrocarboné peut être facultativement remplacé par -O-, -S-, -S(O)-, -SO2-, -NH-, -NCH3- ou -NC(O)CH3- ;
    Z est un aryle ou hétéroaryle ;
    R8 est sélectionné parmi :
    (A) un aryle facultativement substitué par un ou deux groupes sélectionnés parmi :
    (a) un alkyle en C1 à 3 facultativement substitué par -OR9, -NR9R10 ou -NR9SO2R10 ;
    (b) un cycloalkyle en C3 à 7 facultativement substitué par -OR9 ou -NR9R10 ;
    (a) -OR9 ;
    (c) un halogène ;
    (d) -C(O)NR9R10 ;
    (e) -SO2NR9R10 ;
    (f) -NR9(CO)R10 ;
    (g) -SO2R9 ;
    (h) -NR9R10 ;
    (i) -CN ;
    (j) -C(O)OR9 ;
    (k) -NR9SO2R10 ; et
    (l) -C(O)R9 ;
    (B) un hétéroaryle facultativement substitué par un ou deux groupes sélectionnés parmi :
    (a) un alkyle en C1 à 3 facultativement substitué par -OR9, -NR9R10 ou un halogène ;
    (b) un cycloalkyle en C3 à 7 facultativement substitué par -OR9 ou -NR9R10 ;
    (a) -OR9 ;
    (c) un halogène ;
    (d) -C(O)NR9R10 ;
    (e) -SO2NR9R10 ;
    (f) -NR9(CO)R10 ;
    (g) -SO2R9 ;
    (h) -NR9R10 ; et
    (i) -CN ;
    R9 est sélectionné parmi H, un alkyle en C1 à 5 ou un cycloalkyle en C3 à 7 ;
    R10 est sélectionné parmi H, un alkyle en C1 à 5 ou un cycloalkyle en C3 à 7 ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  2. Composé de formule I selon la revendication 1, dans lequel :
    R1 est sélectionné parmi -CN, -OCF3, -Br, -Cl ou -CF3 ;
    R2 est -Cl ou -CF3 ;
    R3 est -F ou H ;
    X est un groupe
    Figure imgb2016
     dans lequel
    R4 est sélectionné parmi :
    (A) un alkyle en C1 à 2 facultativement substitué par -OH ;
    (B) (1-méthyl-1H-imidazol-5-yl)méthyle ; et
    (C) (1-méthyl-1H-imidazol-4-yl)méthyle ;
    R5 est H, ou -CH3 ; ou
    R4 et R5, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 atomes ;
    Y est un groupe
    Figure imgb2017
     dans lequel
    R6 est H ou -CH3 ;
    R7est H ou -CH3 ; ou
    R6 et R7, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 ou 4 atomes ;
    Z est sélectionné parmi :
    (A) pyridinyle ;
    (B) pyrimidinyle ;
    (C) naphtyridinyle ;
    (D) pyridazinyle ; et
    (E) oxadiazolyle ;
    R8 est sélectionné parmi :
    (A) un phényle facultativement substitué par un ou deux groupes sélectionnés parmi :
    (a) -OR9 ;
    (b) -CH2OR9 ;
    (c) -C(O)OH ;
    (d) -C(O)NR9R10 ;
    (e) -SO2CH3 ;
    (f) -NHSO2CH3 ;
    (g) -SO2NR9R10 ;
    (h) -F ;
    (i) -NHC(O)CH3 ;
    (j) -CH2NHSO2CH3 ;
    (k) -C(O)CH3 ;
    (l) -Cl ;
    (m) -CN ;
    (n) -CH3 ;
    (o) -CH2N(CH3)2 ; et
    (p) 1-hydroxycyclopropyle ;
    (B) un pyridinyle facultativement mono ou di-substitué par -CH3, -CH2OH, -NH2, -OH, -Cl, -F, -CN, -CF3 ou un cyclopropyle ;
    (C) 1H-pyrazolyle facultativement mono ou di-substitué par -CH3 ou un cyclopropyle ;
    (D) un pyrimidinyle facultativement substitué par -CH3 ;
    (E) un isoxazolyle facultativement substitué par -CH3 ;
    (F) imidazo[1,2-a]pyridinyle facultativement substitué par -CH3 ;
    (G) 1H-pyrrolo[2,3-b]pyridinyle ;
    (H) un thiazolyle facultativement mono ou di-substitué par -CH3 ou -Cl ;
    (I) un oxadiazolyle facultativement substitué par un cyclopropyle ;
    (J) un furanyle ;
    (K) un quinoléinyle ;
    (L) 1H-imidazolyle facultativement substitué par -CH3 ;
    (M) 1H-triazolyle ;
    (N) 1H-pyrrolyle facultativement substitué par -CH3 ;
    (O) un oxazolyle ; et
    (Q) 1H-indolyle ;
    R9 est H ou -CH3 ;
    R10 est H ou -CH3 ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  3. Composé de formule I selon la revendication 1, dans lequel :
    R1 est sélectionné parmi -CN, -OCF3, -Br, -Cl ou -CF3 ;
    R2 est -Cl ou -CF3 ;
    R3 est -F ou -H ;
    X est un groupe
    Figure imgb2018
     dans lequel
    R4 est sélectionné parmi :
    (A) -CH3 ;
    (B) -CH2OH ;
    (C) -CH(OH)CH3 ;
    (D) (1-méthyl-1H-imidazol-5-yl)méthyle ; et
    (E) (1-méthyl-1H-imidazol-4-yl)méthyle ;
    R5 est H ou -CH3 ; ou
    R4 et R5, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 atomes ;
    Y est un groupe
    Figure imgb2019
     dans lequel
    R6 est -CH3 ;
    R7 est H ou -CH3 ; ou
    R6 et R7, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 ou 4 atomes ;
    Z est sélectionné parmi :
    Figure imgb2020
    R8 est sélectionné parmi :
    (A) un phényle substitué par un groupe sélectionné parmi :
    (a) -OH ;
    (b) -CH2OR9 ;
    (c) -C(O)OH ;
    (d) -C(O)NR9R10 ;
    (e) -SO2CH3 ;
    (f) -NHSO2CH3 ;
    (g) -SO2NH2 ;
    (h) -F ;
    (i) -NHC(O)CH3 ;
    (j) -CH2NHSO2CH3 ; et
    (k) -C(O)CH3 ;
    (B) un pyridinyle facultativement substitué par -CH3, -CH2OH, -NH2, -OH, -Cl, -F, -CN ou un cyclopropyle ;
    (C) 1H-pyrazol-4-yle facultativement mono ou di-substitué par -CH3 ou un cyclopropyle ;
    (D) pyrimidin-5-yle facultativement substitué par -CH3 ;
    (E) isoxazol-4-yle facultativement substitué par -CH3 ;
    (F) 2-imidazol[1,2-a]pyridin-6-yle facultativement substitué par -CH3 ;
    (G) 1H-pyrrolo[2,3-b]pyridin-5-yle ;
    (H) 1H-pyrazol-3-yle ;
    (I) thiazol-5-yle facultativement substitué par -CH3 ;
    (J) thiazol-4-yle ;
    (K) 2-cyclopropyl-1,3,4-oxadiazol-5-yle ;
    (L) furan-3-yle ;
    (M) quinoléin-3-yle ;
    (N) 1H-imidazol-2-yle facultativement substitué par -CH3 ;
    (O) 1-méthyl-1H-imidazol-5-yle ;
    (P) 1H-imidazolyle ; et
    (Q) 1H-1,2,4-triazolyle ;
    R9 est H ou -CH3 ;
    R10 est H ou -CH3 ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  4. Composé de formule I selon la revendication 1, dans lequel :
    R1 est sélectionné parmi -CN, -OCF3 ou -Br ;
    R2 est -Cl ou -CF3 ;
    R3 est -F ou -H ;
    X est un groupe
    Figure imgb2021
     dans lequel
    R4 est sélectionné parmi :
    (A) -CH3 ;
    (B) -CH2OH ; et
    (C) -CH(OH)CH3 ;
    R5 est H ; ou
    R4 et R5, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 atomes ;
    Y est un groupe
    Figure imgb2022
     dans lequel
    R6 est -CH3 ;
    R7 est H ; ou
    R6 et R7, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 ou 4 atomes ;
    Z est sélectionné parmi :
    Figure imgb2023
    R8 est sélectionné parmi :
    (A) un phényle substitué par un groupe sélectionné parmi :
    (a) -OH ;
    (b) -CH2OH ;
    (c) -C(O)OH ;
    (d) -C(O)NR9R10 ;
    (e) -SO2CH3 ;
    (f) -NHSO2CH3 ; et
    (g) -SO2NH2 ;
    (B) un pyridinyle facultativement substitué par -CH3, -CH2OH, -NH2, -OH, -Cl, -F ;
    (C) 1H-pyrazol-4-yle facultativement mono ou di-substitué par -CH3 ou un cyclopropyle ;
    (D) 2-méthyl-pyrimidin-5-yle ;
    (E) isoxazol-4-yle ;
    (F) imidazol[1,2-a]pyridin-6-yle ; et
    (G) 1H-pyrrolo[2,3-b]pyridin-5-yle ;
    R9 est H ou -CH3 ;
    R10 est H ou -CH3 ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  5. Composé de formule I selon la revendication 1, dans lequel :
    R1 est sélectionné parmi -CN et -OCF3 ;
    R2 est -Cl ;
    R3 est -F ;
    X est un groupe
    Figure imgb2024
     dans lequel
    R4 est -CH3 ou -CH(OH)CH3 ;
    R5 est H ; ou
    R4 et R5, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 atomes ; Y est un groupe
    Figure imgb2025
     dans lequel
    R6 est -CH3 ;
    R7 est H ; ou
    R6 et R7, conjointement avec le carbone auquel ils sont attachés, forment un cycle hydrocarboné saturé de 3 ou 4 atomes ;
    Z est sélectionné parmi :
    Figure imgb2026
    R8 est sélectionné parmi :
    (A) un phényle substitué par un groupe sélectionné parmi :
    (a) -OH ; et
    (b) -CH2OH ;
    (B) pyridin-3-yle substitué en position 6 par -CH3 ou -CH2OH ; et
    (C) 1H-pyrazol-4-yle facultativement mono ou di-substitué par -CH3 ;
    ou un sel pharmaceutiquement acceptable de celui-ci.
  6. Composé sélectionné parmi les composés du tableau 1 suivant : Tableau 1
    Figure imgb2027
         Composé R1 R2 R3 X Y Z R8 1 CN Cl F
    Figure imgb2028
    Figure imgb2029
    Figure imgb2030
    Figure imgb2031
         2 CN Cl F
    Figure imgb2032
    Figure imgb2033
    Figure imgb2034
    Figure imgb2035
         3 CN Cl F
    Figure imgb2036
    Figure imgb2037
    Figure imgb2038
    Figure imgb2039
         4 OCF3 Cl F
    Figure imgb2040
    Figure imgb2041
    Figure imgb2042
    Figure imgb2043
         5 CN Cl F
    Figure imgb2044
    Figure imgb2045
    Figure imgb2046
    Figure imgb2047
         6 CN Cl F
    Figure imgb2048
    Figure imgb2049
    Figure imgb2050
    Figure imgb2051
         7 OCF3 Cl F
    Figure imgb2052
    Figure imgb2053
    Figure imgb2054
    Figure imgb2055
         8 OCF3 Cl F
    Figure imgb2056
    Figure imgb2057
    Figure imgb2058
    Figure imgb2059
         9 CN Cl H
    Figure imgb2060
    Figure imgb2061
    Figure imgb2062
    Figure imgb2063
         10 CN Cl F
    Figure imgb2064
    Figure imgb2065
    Figure imgb2066
    Figure imgb2067
         11 CN Cl F
    Figure imgb2068
    Figure imgb2069
    Figure imgb2070
    Figure imgb2071
         12 OCF3 Cl F
    Figure imgb2072
    Figure imgb2073
    Figure imgb2074
    Figure imgb2075
         13 CN Cl F
    Figure imgb2076
    Figure imgb2077
    Figure imgb2078
    Figure imgb2079
         14 CN Cl F
    Figure imgb2080
    Figure imgb2081
    Figure imgb2082
    Figure imgb2083
         15 CN Cl F
    Figure imgb2084
    Figure imgb2085
    Figure imgb2086
    Figure imgb2087
         16 CN Cl F
    Figure imgb2088
    Figure imgb2089
    Figure imgb2090
    Figure imgb2091
         17 OCF3 Cl F
    Figure imgb2092
    Figure imgb2093
    Figure imgb2094
    Figure imgb2095
         18 CN Cl F
    Figure imgb2096
    Figure imgb2097
    Figure imgb2098
    Figure imgb2099
         19 CN Cl F
    Figure imgb2100
    Figure imgb2101
    Figure imgb2102
    Figure imgb2103
         20 OCF3 Cl F
    Figure imgb2104
    Figure imgb2105
    Figure imgb2106
    Figure imgb2107
         21 CN Cl F
    Figure imgb2108
    Figure imgb2109
    Figure imgb2110
    Figure imgb2111
         22 CN Cl H
    Figure imgb2112
    Figure imgb2113
    Figure imgb2114
    Figure imgb2115
         23 CN Cl F
    Figure imgb2116
    Figure imgb2117
    Figure imgb2118
    Figure imgb2119
         24 OCF3 Cl H
    Figure imgb2120
    Figure imgb2121
    Figure imgb2122
    Figure imgb2123
         25 CN Cl F
    Figure imgb2124
    Figure imgb2125
    Figure imgb2126
    Figure imgb2127
         26 CF3 Cl H
    Figure imgb2128
    Figure imgb2129
    Figure imgb2130
    Figure imgb2131
         27 CN Cl F
    Figure imgb2132
    Figure imgb2133
    Figure imgb2134
    Figure imgb2135
         28 OCF3 Cl F
    Figure imgb2136
    Figure imgb2137
    Figure imgb2138
    Figure imgb2139
         29 CN Cl F
    Figure imgb2140
    Figure imgb2141
    Figure imgb2142
    Figure imgb2143
         30 CN Cl F
    Figure imgb2144
    Figure imgb2145
    Figure imgb2146
    Figure imgb2147
         31 CN Cl F
    Figure imgb2148
    Figure imgb2149
    Figure imgb2150
    Figure imgb2151
         32 CN Cl F
    Figure imgb2152
    Figure imgb2153
    Figure imgb2154
    Figure imgb2155
         33 CN Cl F
    Figure imgb2156
    Figure imgb2157
    Figure imgb2158
    Figure imgb2159
         34 CN Cl F
    Figure imgb2160
    Figure imgb2161
    Figure imgb2162
    Figure imgb2163
         35 CN Cl F
    Figure imgb2164
    Figure imgb2165
    Figure imgb2166
    Figure imgb2167
         36 CN Cl F
    Figure imgb2168
    Figure imgb2169
    Figure imgb2170
    Figure imgb2171
         37 CN Cl F
    Figure imgb2172
    Figure imgb2173
    Figure imgb2174
    Figure imgb2175
         38 CN Cl F
    Figure imgb2176
    Figure imgb2177
    Figure imgb2178
    Figure imgb2179
         39 OCF3 Cl F
    Figure imgb2180
    Figure imgb2181
    Figure imgb2182
    Figure imgb2183
         40 OCF3 Cl F
    Figure imgb2184
    Figure imgb2185
    Figure imgb2186
    Figure imgb2187
         41 OCF3 Cl F
    Figure imgb2188
    Figure imgb2189
    Figure imgb2190
    Figure imgb2191
         42 OCF3 Cl F
    Figure imgb2192
    Figure imgb2193
    Figure imgb2194
    Figure imgb2195
         43 CN Cl F
    Figure imgb2196
    Figure imgb2197
    Figure imgb2198
    Figure imgb2199
         44 CN Cl F
    Figure imgb2200
    Figure imgb2201
    Figure imgb2202
    Figure imgb2203
         45 CN Cl F
    Figure imgb2204
    Figure imgb2205
    Figure imgb2206
    Figure imgb2207
         46 OCF3 Cl F
    Figure imgb2208
    Figure imgb2209
    Figure imgb2210
    Figure imgb2211
         47 OCF3 Cl F
    Figure imgb2212
    Figure imgb2213
    Figure imgb2214
    Figure imgb2215
         48 OCF3 Cl F
    Figure imgb2216
    Figure imgb2217
    Figure imgb2218
    Figure imgb2219
         49 OCF3 Cl F
    Figure imgb2220
    Figure imgb2221
    Figure imgb2222
    Figure imgb2223
         50 CN Cl F
    Figure imgb2224
    Figure imgb2225
    Figure imgb2226
    Figure imgb2227
         51 CN CF3 H
    Figure imgb2228
    Figure imgb2229
    Figure imgb2230
    Figure imgb2231
         52 CN Cl H
    Figure imgb2232
    Figure imgb2233
    Figure imgb2234
    Figure imgb2235
         53 CN Cl H
    Figure imgb2236
    Figure imgb2237
    Figure imgb2238
    Figure imgb2239
         54 CN Cl H
    Figure imgb2240
    Figure imgb2241
    Figure imgb2242
    Figure imgb2243
         55 CN Cl H
    Figure imgb2244
    Figure imgb2245
    Figure imgb2246
    Figure imgb2247
         56 CN Cl H
    Figure imgb2248
    Figure imgb2249
    Figure imgb2250
    Figure imgb2251
         57 CN Cl H
    Figure imgb2252
    Figure imgb2253
    Figure imgb2254
    Figure imgb2255
         58 CN Cl H
    Figure imgb2256
    Figure imgb2257
    Figure imgb2258
    Figure imgb2259
         59 CN Cl H
    Figure imgb2260
    Figure imgb2261
    Figure imgb2262
    Figure imgb2263
         60 CN Cl H
    Figure imgb2264
    Figure imgb2265
    Figure imgb2266
    Figure imgb2267
         61 CN Cl H
    Figure imgb2268
    Figure imgb2269
    Figure imgb2270
    Figure imgb2271
         62 CN Cl H
    Figure imgb2272
    Figure imgb2273
    Figure imgb2274
    Figure imgb2275
         63 CN Cl H
    Figure imgb2276
    Figure imgb2277
    Figure imgb2278
    Figure imgb2279
         64 CN Cl F
    Figure imgb2280
    Figure imgb2281
    Figure imgb2282
    Figure imgb2283
         65 CN Cl F
    Figure imgb2284
    Figure imgb2285
    Figure imgb2286
    Figure imgb2287
         66 CN Cl H
    Figure imgb2288
    Figure imgb2289
    Figure imgb2290
    Figure imgb2291
         67 CN Cl H
    Figure imgb2292
    Figure imgb2293
    Figure imgb2294
    Figure imgb2295
         68 CN Cl F
    Figure imgb2296
    Figure imgb2297
    Figure imgb2298
    Figure imgb2299
         69 CN Cl F
    Figure imgb2300
    Figure imgb2301
    Figure imgb2302
    Figure imgb2303
         70 CN Cl F
    Figure imgb2304
    Figure imgb2305
    Figure imgb2306
    Figure imgb2307
         71 CN Cl H
    Figure imgb2308
    Figure imgb2309
    Figure imgb2310
    Figure imgb2311
         72 CN Cl F
    Figure imgb2312
    Figure imgb2313
    Figure imgb2314
    Figure imgb2315
         73 CN Cl F
    Figure imgb2316
    Figure imgb2317
    Figure imgb2318
    Figure imgb2319
         74 CN Cl F
    Figure imgb2320
    Figure imgb2321
    Figure imgb2322
    Figure imgb2323
         75 Br Cl H
    Figure imgb2324
    Figure imgb2325
    Figure imgb2326
    Figure imgb2327
         76 Cl Cl H
    Figure imgb2328
    Figure imgb2329
    Figure imgb2330
    Figure imgb2331
         77 CN Cl F
    Figure imgb2332
    Figure imgb2333
    Figure imgb2334
    Figure imgb2335
         78 CN Cl F
    Figure imgb2336
    Figure imgb2337
    Figure imgb2338
    Figure imgb2339
         79 CN Cl H
    Figure imgb2340
    Figure imgb2341
    Figure imgb2342
    Figure imgb2343
         80 CN Cl H
    Figure imgb2344
    Figure imgb2345
    Figure imgb2346
    Figure imgb2347
         81 CN Cl H
    Figure imgb2348
    Figure imgb2349
    Figure imgb2350
    Figure imgb2351
         82 CN Cl H
    Figure imgb2352
    Figure imgb2353
    Figure imgb2354
    Figure imgb2355
         83 CN Cl H
    Figure imgb2356
    Figure imgb2357
    Figure imgb2358
    Figure imgb2359
         84 CN Cl H
    Figure imgb2360
    Figure imgb2361
    Figure imgb2362
    Figure imgb2363
         85 CN Cl F
    Figure imgb2364
    Figure imgb2365
    Figure imgb2366
    Figure imgb2367
         86 OCF3 Cl F
    Figure imgb2368
    Figure imgb2369
    Figure imgb2370
    Figure imgb2371
         87 CN Cl F
    Figure imgb2372
    Figure imgb2373
    Figure imgb2374
    Figure imgb2375
         88 CN Cl F
    Figure imgb2376
    Figure imgb2377
    Figure imgb2378
    Figure imgb2379
         89 OCF3 Cl F
    Figure imgb2380
    Figure imgb2381
    Figure imgb2382
    Figure imgb2383
         90 CN Cl F
    Figure imgb2384
    Figure imgb2385
    Figure imgb2386
    Figure imgb2387
         91 CN Cl H
    Figure imgb2388
    Figure imgb2389
    Figure imgb2390
    Figure imgb2391
         92 CN Cl H
    Figure imgb2392
    Figure imgb2393
    Figure imgb2394
    Figure imgb2395
         93 CN Cl F
    Figure imgb2396
    Figure imgb2397
    Figure imgb2398
    Figure imgb2399
         94 CN Cl F
    Figure imgb2400
    Figure imgb2401
    Figure imgb2402
    Figure imgb2403
         95 CN Cl F
    Figure imgb2404
    Figure imgb2405
    Figure imgb2406
    Figure imgb2407
         96 CN Cl F
    Figure imgb2408
    Figure imgb2409
    Figure imgb2410
    Figure imgb2411
         97 OCF3 Cl H
    Figure imgb2412
    Figure imgb2413
    Figure imgb2414
    Figure imgb2415
         98 CN Cl H
    Figure imgb2416
    Figure imgb2417
    Figure imgb2418
    Figure imgb2419
         99 OCF3 Cl F
    Figure imgb2420
    Figure imgb2421
    Figure imgb2422
    Figure imgb2423
         100 CN Cl F
    Figure imgb2424
    Figure imgb2425
    Figure imgb2426
    Figure imgb2427
         101 CN Cl F
    Figure imgb2428
    Figure imgb2429
    Figure imgb2430
    Figure imgb2431
         102 CN Cl F
    Figure imgb2432
    Figure imgb2433
    Figure imgb2434
    Figure imgb2435
         103 OCF3 Cl H
    Figure imgb2436
    Figure imgb2437
    Figure imgb2438
    Figure imgb2439
         104 OCF3 Cl F
    Figure imgb2440
    Figure imgb2441
    Figure imgb2442
    Figure imgb2443
         105 CN Cl F
    Figure imgb2444
    Figure imgb2445
    Figure imgb2446
    Figure imgb2447
         106 CN Cl F
    Figure imgb2448
    Figure imgb2449
    Figure imgb2450
    Figure imgb2451
         107 CN Cl F
    Figure imgb2452
    Figure imgb2453
    Figure imgb2454
    Figure imgb2455
         108 OCF3 Cl F
    Figure imgb2456
    Figure imgb2457
    Figure imgb2458
    Figure imgb2459
         109 CN Cl F
    Figure imgb2460
    Figure imgb2461
    Figure imgb2462
    Figure imgb2463
         110 OCF3 Cl F
    Figure imgb2464
    Figure imgb2465
    Figure imgb2466
    Figure imgb2467
         111 CN Cl F
    Figure imgb2468
    Figure imgb2469
    Figure imgb2470
    Figure imgb2471
         112 CN Cl F
    Figure imgb2472
    Figure imgb2473
    Figure imgb2474
    Figure imgb2475
         113 CN Cl F
    Figure imgb2476
    Figure imgb2477
    Figure imgb2478
    Figure imgb2479
         114 CN Cl F
    Figure imgb2480
    Figure imgb2481
    Figure imgb2482
    Figure imgb2483
         115 CN Cl F
    Figure imgb2484
    Figure imgb2485
    Figure imgb2486
    Figure imgb2487
         116 OCF3 Cl F
    Figure imgb2488
    Figure imgb2489
    Figure imgb2490
    Figure imgb2491
         117 CN Cl F
    Figure imgb2492
    Figure imgb2493
    Figure imgb2494
    Figure imgb2495
         118 OCF3 Cl F
    Figure imgb2496
    Figure imgb2497
    Figure imgb2498
    Figure imgb2499
         119 CN Cl F
    Figure imgb2500
    Figure imgb2501
    Figure imgb2502
    Figure imgb2503
         120 OCF3 Cl F
    Figure imgb2504
    Figure imgb2505
    Figure imgb2506
    Figure imgb2507
         121 CN Cl F
    Figure imgb2508
    Figure imgb2509
    Figure imgb2510
    Figure imgb2511
         122 CN Cl F
    Figure imgb2512
    Figure imgb2513
    Figure imgb2514
    Figure imgb2515
         123 CN Cl F
    Figure imgb2516
    Figure imgb2517
    Figure imgb2518
    Figure imgb2519
         124 CN Cl H
    Figure imgb2520
    Figure imgb2521
    Figure imgb2522
    Figure imgb2523
         125 OCF3 Cl F
    Figure imgb2524
    Figure imgb2525
    Figure imgb2526
    Figure imgb2527
         126 CN Cl H
    Figure imgb2528
    Figure imgb2529
    Figure imgb2530
    Figure imgb2531
         127 CN Cl H
    Figure imgb2532
    Figure imgb2533
    Figure imgb2534
    Figure imgb2535
         128 CN Cl H
    Figure imgb2536
    Figure imgb2537
    Figure imgb2538
    Figure imgb2539
         129 CN Cl H
    Figure imgb2540
    Figure imgb2541
    Figure imgb2542
    Figure imgb2543
         130 CN Cl H
    Figure imgb2544
    Figure imgb2545
    Figure imgb2546
    Figure imgb2547
         131 CN Cl H
    Figure imgb2548
    Figure imgb2549
    Figure imgb2550
    Figure imgb2551
         132 CN Cl H
    Figure imgb2552
    Figure imgb2553
    Figure imgb2554
    Figure imgb2555
         133 CN Cl H
    Figure imgb2556
    Figure imgb2557
    Figure imgb2558
    Figure imgb2559
         134 CN Cl H
    Figure imgb2560
    Figure imgb2561
    Figure imgb2562
    Figure imgb2563
         135 CN Cl H
    Figure imgb2564
    Figure imgb2565
    Figure imgb2566
    Figure imgb2567
         136 CN Cl H
    Figure imgb2568
    Figure imgb2569
    Figure imgb2570
    Figure imgb2571
         137 CN Cl H
    Figure imgb2572
    Figure imgb2573
    Figure imgb2574
    Figure imgb2575
         138 CN Cl H
    Figure imgb2576
    Figure imgb2577
    Figure imgb2578
    Figure imgb2579
         139 CN Cl H
    Figure imgb2580
    Figure imgb2581
    Figure imgb2582
    Figure imgb2583
         140 CN Cl H
    Figure imgb2584
    Figure imgb2585
    Figure imgb2586
    Figure imgb2587
         141 CN Cl H
    Figure imgb2588
    Figure imgb2589
    Figure imgb2590
    Figure imgb2591
         142 CN Cl H
    Figure imgb2592
    Figure imgb2593
    Figure imgb2594
    Figure imgb2595
         143 CN Cl H
    Figure imgb2596
    Figure imgb2597
    Figure imgb2598
    Figure imgb2599
         144 CN Cl H
    Figure imgb2600
    Figure imgb2601
    Figure imgb2602
    Figure imgb2603
         145 CN Cl F
    Figure imgb2604
    Figure imgb2605
    Figure imgb2606
    Figure imgb2607
         146 CN Cl H
    Figure imgb2608
    Figure imgb2609
    Figure imgb2610
    Figure imgb2611
         147 CN Cl H
    Figure imgb2612
    Figure imgb2613
    Figure imgb2614
    Figure imgb2615
         148 CN Cl H
    Figure imgb2616
    Figure imgb2617
    Figure imgb2618
    Figure imgb2619
         149 CN Cl H
    Figure imgb2620
    Figure imgb2621
    Figure imgb2622
    Figure imgb2623
         150 OCF3 Cl F
    Figure imgb2624
    Figure imgb2625
    Figure imgb2626
    Figure imgb2627
         151 CN Cl F
    Figure imgb2628
    Figure imgb2629
    Figure imgb2630
    Figure imgb2631
         152 CN Cl F
    Figure imgb2632
    Figure imgb2633
    Figure imgb2634
    Figure imgb2635
         153 OCF3 Cl F
    Figure imgb2636
    Figure imgb2637
    Figure imgb2638
    Figure imgb2639
         154 CN Cl F
    Figure imgb2640
    Figure imgb2641
    Figure imgb2642
    Figure imgb2643
         155 CN Cl F
    Figure imgb2644
    Figure imgb2645
    Figure imgb2646
    Figure imgb2647
         156 CN Cl F
    Figure imgb2648
    Figure imgb2649
    Figure imgb2650
    Figure imgb2651
         157 CN Cl F
    Figure imgb2652
    Figure imgb2653
    Figure imgb2654
    Figure imgb2655
         158 CN Cl F
    Figure imgb2656
    Figure imgb2657
    Figure imgb2658
    Figure imgb2659
         159 CN Cl F
    Figure imgb2660
    Figure imgb2661
    Figure imgb2662
    Figure imgb2663
         160 CN Cl F
    Figure imgb2664
    Figure imgb2665
    Figure imgb2666
    Figure imgb2667
    Ou un sel pharmaceutiquement acceptable de celui-ci.
  7. Composé selon la revendication 6, sélectionné parmi les composés 1, 2, 4 à 8, 10 à 16, 18, 20, 21, 23, 27, 28, 30 à 35, 37 à 47, 49 à 52, 54, 56, 58, 60 à 62, 64 à 66, 68 à 70, 72, 75, 78, 87 à 90, 93, 96, 100, 101, 103 à 106, 108 à 112, 115 à 121, 123, 125, 127, 129, 131 à 136, 138, 141 à 143, 145, 146 et 149 à 160 ou sel pharmaceutiquement acceptable de celui-ci.
  8. Composition pharmaceutique comprenant un composé selon la revendication 1, ou sel pharmaceutiquement acceptable de celui-ci, et au moins un support ou adjuvant pharmaceutiquement acceptable.
  9. Composé selon la revendication 1 pour son utilisation en tant que médicament.
  10. Composé selon la revendication 1 pour son utilisation en tant que médicament pour le traitement d'une inflammation ou d'un état inflammatoire.
  11. Composé selon la revendication 1 pour son utilisation en tant que médicament pour le traitement du syndrome de détresse respiratoire de l'adulte, d'un choc, d'une toxicité à l'oxygène, du syndrome de lésions d'organes multiples consécutif à une septicémie, du syndrome de lésions d'organes multiples consécutif à un traumatisme, d'une lésion de reperfusion du tissu due à une dérivation cardiopulmonaire, d'un infarctus du myocarde, d'une glomérulonéphrite aiguë, d'une vascularite, d'une arthrite réactionnelle, d'une dermatose avec des composantes inflammatoires aiguës, d'un accident vasculaire cérébral, d'une lésion thermique, d'une hémodialyse, d'une leucophérèse, de l'entérocolite nécrosante ou d'un syndrome associé à une transfusion de granulocytes, du psoriasis, du rejet de greffe d'organes/tissus, de la réaction du greffon contre l'hôte, d'une maladie auto-immune, du syndrome de Raynaud, de la thyroïdite auto-immune, d'une dermatite, de la sclérose en plaques, de la polyarthrite rhumatoïde, du diabète sucré insulino-dépendant, d'une uvéite, d'une maladie intestinale inflammatoire, de la maladie de Crohn, de la colite ulcéreuse, du lupus érythémateux systémique ou de l'asthme.
EP10720512.2A 2009-06-02 2010-05-26 DÉRIVÉS AMIDES DE L'ACIDE 6,7-DIHYDRO-5H-IMIDAZO[1,2-a]IMIDAZOLE-3-CARBOXYLIQUE Active EP2445909B1 (fr)

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JP5384733B2 (ja) 2009-06-02 2014-01-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ６，７−ジヒドロ−５Ｈ−イミダゾ［１，２−ａ］イミダゾール−３−カルボン酸アミドの誘導体
WO2018166855A1 (fr) 2017-03-16 2018-09-20 Basf Se Dihydroisoxazoles à substitution hétérobicyclique
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Family Cites Families (41)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2015493A1 (fr) 1968-08-12 1970-04-30 Sumitomo Chemical Co
DK123717B (da) 1968-11-25 1972-07-24 Sumitomo Chemical Co 3-(3',5'-Dihalogenphenyl)-imidazolidin-2,4-dionderivater med mirobicid virkning.
JPS5136332B1 (fr) 1970-12-09 1976-10-07
EP0091596B1 (fr) 1982-04-08 1991-09-11 Shell Internationale Researchmaatschappij B.V. Hydantoins, préparation et application
JPS63270665A (ja) 1987-04-30 1988-11-08 Wakamoto Pharmaceut Co Ltd イミダゾ−ル誘導体
JPS63270667A (ja) 1987-04-30 1988-11-08 Wakamoto Pharmaceut Co Ltd １−ベンジルイミダゾ−ル誘導体
US5208250A (en) 1988-05-25 1993-05-04 Warner-Lambert Company Known and selected novel arylmethylenyl derivatives of thiazolidinones, imidazolidinones and oxazolidinones useful as antiallergy agents and anti-inflammatory agents
US5306822A (en) 1988-05-25 1994-04-26 Warner-Lambert Company Arylmethylenyl derivatives of oxazolidinone
IE940525L (en) 1988-05-25 1989-11-25 Warner Lambert Co Known and selected novel arylmethylenyl derivatives of¹thiazolidinones, imidazolidinones and oxazolidinones useful¹as antiallergy agents and antiinflammatory agents
US4977270A (en) 1988-12-01 1990-12-11 Ici Americas Inc. Substituted 2,4-dioxodiazolidines and -thiadiazolidines and their use as herbicides
US4911748A (en) 1988-12-22 1990-03-27 Ici Americas Inc. Herbicidal 5-substituted-3-phenyl-imidazolidine-2,4-diones
JPH04273877A (ja) 1991-02-28 1992-09-30 Sumitomo Pharmaceut Co Ltd 新規なイミダゾール誘導体
EP0545478A1 (fr) 1991-12-03 1993-06-09 MERCK SHARP & DOHME LTD. Composés hétérocycliques comme tachykinine antagonistes
JPH05188631A (ja) 1992-01-10 1993-07-30 Mita Ind Co Ltd 電子写真感光体
TW521073B (en) 1994-01-05 2003-02-21 Hoechst Marion Roussel Inc New optionally substituted phenylimidazolidines, their preparation process, their use as anti-androgenic agent and the pharmaceutical compositions containing them
US20040006011A1 (en) 1996-07-12 2004-01-08 Gour Barbara J. Peptidomimetic modulators of cell adhesion
WO1998018324A1 (fr) 1996-10-28 1998-05-07 The University Of Washington Induction d'une mutation virale par incorporation d'analogues de ribonucleosides a defaut de codage dans un arn viral
US6355664B1 (en) 1997-03-03 2002-03-12 Boehringer Ingelheim Pharmaceuticals, Inc. Phenylpyrrolidines, phenylimidazolidines, 3-phenyl-1,3-oxizolidines and 3-phenyl-1,3-thiazolidines and their use in the treatment of inflammatory disease
IL130931A0 (en) 1997-03-03 2001-01-28 Boehringer Ingelheim Pharma Small molecules useful in the treatment of inflammatory disease
PT1007033E (pt) 1997-08-28 2008-07-22 Novartis Ag Antagonistas do antigénio-1 da função de linfócitos
BR9909418A (pt) 1998-03-27 2001-09-25 Genentech Inc Antagonistas para o tratamento de distúrbios mediados por receptor de aderência cd11/cd18 e método para tratar ou melhorar uma resposta ou distúrbio imunológico ou inflamatório em um mamìfero mediada através da famìlia cd11/cd18 em moléculas de aderência celular
WO2000066618A1 (fr) * 1999-04-28 2000-11-09 Basf Aktiengesellschaft Antagonistes recepteurs d'integrine
US6350763B1 (en) 1999-07-21 2002-02-26 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammation disease
WO2001007044A1 (fr) 1999-07-21 2001-02-01 Boehringer Ingelheim Pharmaceuticals, Inc. Petites molecules utiles pour le traitement de maladies inflammatoires
US6492408B1 (en) 1999-07-21 2002-12-10 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
ATE396722T1 (de) 1999-07-21 2008-06-15 Boehringer Ingelheim Pharma Kleine moleküle zur behandlung von endzündlichen erkrankungen
US6365615B1 (en) 1999-07-21 2002-04-02 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful in the treatment of inflammatory disease
ATE292634T1 (de) 1999-10-20 2005-04-15 Tanabe Seiyaku Co Inhibitoren der alpha-l beta-2 vermittelten zelladhäsion
WO2002050080A1 (fr) 2000-12-19 2002-06-27 Boehringer Ingelheim Pharmaceuticals, Inc. Petites molecules utiles dans le traitement de maladies inflammatoires
ATE316954T1 (de) * 2002-02-08 2006-02-15 Merck & Co Inc N-biphenylmethylaminocycloalkancarboxamid- derivative
US20030232817A1 (en) 2002-05-29 2003-12-18 Boehringer Ingelheim Pharmaceuticals, Inc. Small molecules useful for the treatment of inflammatory disease
IL166426A0 (en) * 2002-08-29 2006-01-15 Merck & Co Inc N-biarylmethyl aminocycloalkanecarboxamide derivatives
US6844360B2 (en) * 2002-10-30 2005-01-18 Boehringer Ingelheim Pharmaceuticals, Inc. Derivatives of [6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonylamino]-propionamide
US6852748B1 (en) 2002-10-30 2005-02-08 Boehringer Ingelheim Pharmaceuticals, Inc. Derivatives of [6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonyl]-pyrrolidine-2-carboxylic acid amide
US7470795B2 (en) 2004-07-27 2008-12-30 Boehringer Ingelheim Pharmaceuticals, Inc. Synthesis of 6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-sulfonic acid amides
JP2008534685A (ja) 2005-04-05 2008-08-28 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 炎症性疾患の治療に有用な置換ベンジルイミダゾール
WO2006107941A1 (fr) 2005-04-06 2006-10-12 Boehringer Ingelheim International Gmbh Derives d'amides, esters et acides [6,7-dihydro-5h-imidazo [1,2-alpha]imidazole-3-sulfonyl]-azetedino-carboxyliques et leur utilisation comme anti-inflammatoires
BRPI0610354A2 (pt) 2005-05-19 2010-06-15 Boehringer Ingelheim Internac derivados de ácido 6,7-diidro-5h-imidazo[1,2-a]imidazol-3-slfÈnico, bem como composição farmacêutica e uso dos mesmos
NZ585640A (en) 2007-11-29 2011-03-31 Boehringer Ingelhelheim Internat Gmbh Derivatives of 6,7-dihydro-5h-imidazo[1,2-alpha]imidazole-3- carboxylic acid amides
WO2009083925A1 (fr) 2007-12-28 2009-07-09 Nxp B.V. Dispositif et approche pour un traitement de données d'image basé sur un mouvement
JP5384733B2 (ja) 2009-06-02 2014-01-08 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング ６，７−ジヒドロ−５Ｈ−イミダゾ［１，２−ａ］イミダゾール−３−カルボン酸アミドの誘導体

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TW201109332A (en) 2011-03-16
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AU2010256994A1 (en) 2011-11-03
IL215521A0 (en) 2011-12-29
PL2445909T3 (pl) 2014-04-30
EP2445909A1 (fr) 2012-05-02
US20120252817A1 (en) 2012-10-04
CL2011003076A1 (es) 2012-08-17
WO2010141273A1 (fr) 2010-12-09
KR20120024699A (ko) 2012-03-14
EA019990B1 (ru) 2014-07-30
JP5384732B2 (ja) 2014-01-08
US8575360B2 (en) 2013-11-05
TWI443099B (zh) 2014-07-01
EA201101702A1 (ru) 2012-08-30
BRPI1012581A2 (pt) 2016-03-29
CN102448960A (zh) 2012-05-09
MX2011012717A (es) 2011-12-14
DK2445909T3 (da) 2014-02-10
NZ595622A (en) 2014-02-28
JP2012528859A (ja) 2012-11-15
AR076942A1 (es) 2011-07-20

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